Quaternary ammonium salts of aromatic amine compounds, their preparation and pharmaceutical compositions in which they are present

ABSTRACT

Amine compounds of the formula (Ia):    &lt;IMAGE&gt;  (Ia)  where m, Ar&#39;, N, T and Z are defined herein and J is a group   &lt;IMAGE&gt;   are useful as precursors in the production of quaternary amines and for the treatment of pathological phenomena involving the neurokin system.

This application is a divisional of application Ser. No. 08/345,341,filed Nov. 21, 1994, U.S. Pat. No. 5,674,881, which is a continuation ofSer. No. 08/026,154, filed Mar. 3, 1993 now abandoned.

The present invention relates to novel quaternary ammonium salts ofaromatic derivatives substituted by an amino group and by various ester,amine or amide groups, and to their enantiomers.

The present invention further relates to the method of preparing thecompounds and to the use of the compounds according to the invention incompositions for therapeutic use and more particularly in pathologicalphenomena involving the neurokinin system, such as: pain (D. Regoli etal., Life Sciences, 1987, 40, 109-117), allergy and inflammation (J. E.Morlay et al., Life Sciences, 1987, 41, 527-544), circulatoryinsufficiency (J. Losay et al., 1977, Substance P, Von Euler, U. S. andPernow ed., 287-293, Raven Press, New York), gastrointestinal disorders(D. Regoli et al., Trends Pharmacol. Sci., 1985, 6, 481-484) andrespiratory disorders (J. Mizrahi et al., Pharmacology, 1982, 25,39-50).

Ligands endogenous to the neurokinin receptors have been described, suchas substance P (SP), neurokinin A (NKA) (S. J. Bailey et al., 1983,Substance P, P. Skrabanck ed., 16-17 Boole Press, Dublin) and neurokininB (NKB) (S. P. Watson, Life Sciences, 1983, 25, 797-808).

The neurokinin receptors have been recognized on numerous preparationsand are currently classed in three types: NK₁, NK₂ and NK₃. Whereas themajority of preparations studied hitherto have several types ofreceptor, such as guinea-pig ileum (NK₁, NK₂ and NK₃), some of them aresaid to possess only one type, such as dog carotid artery (NK₁), rabbitpulmonary artery devoid of endothelium (NK₂) and rat portal vein (NK₃)(D. Regoli et al., Trends Pharmacol. Sci., 1988, 38, 1-15).

A more precise characterization of the different receptors is madepossible by the recent synthesis of selective agonists. ThusSar⁹,Met-(O₂)¹¹ !-SP, Nle¹⁰ !-NK₄₋₁₀ and MePhe⁷ !-NKB are said to beselective for the NK₁, NK₂ and NK₃ receptors respectively (cf. D.Regoli, 1988 and 1989, op. cit.).

The NK₂ receptor and neurokinin A, for example, are involved inneurogenic inflammations of the respiratory tract (P. J. Barnes, Arch.Int. Pharmacodyn., 1990, 303, 67-82, and G. F. Joos et al., Arch. Int.Pharmacodyn., 1990, 303, 132-146).

The patent application EP-A-336230 describes peptide derivatives whichare substance P and neurokinin A antagonists and are useful for thetreatment and prevention of asthma.

The international patent applications WO 90/05525, WO 90/05729, WO91/09844 and WO 91/18899 and the European patent applicationsEP-A-436334, EP-A-429466 and EP-A-430771 describe substance Pantagonists.

It has now been found that certain quaternary ammonium salts of aromaticamine compounds possess valuable pharmacological properties asneurokinin receptor antagonists and are useful especially for thetreatment of any pathological condition dependent on substance P andneurokinin.

By using a non-peptide substance P antagonist, CP 96,345, Snider et al.(Sciences, 1991, 251, 435-437) have shown that the affinity of such anagonist for the substance P receptors depends very largely on the animalspecies. Thus, according to these authors, CP 96,345 has a Ki of 240 nMfor the rat receptor (3H-SP binding on rat cortical membranes) but a Kiof 3 nM for the bovine receptor (3H-SP binding on bovine caudalmembrane). Other authors have shown that CP 96,345 has a Ki of 0.4 nM insubstance P binding assays on IM9 and U373 MG human lymphoblastic cells(Gitter et al., Eur. J. Pharmacol., 1991, 197, 237-238).

More particularly, it has been found that certain quaternary ammoniumsalts, including especially those of the compounds claimed in the patentapplications EP-A-428434 and EP 474561, have an increased affinity forthe substance P receptors on human cells of the IM9 line.

It has also been found that, totally surprisingly, these quaternaryammonium salts show a considerable increase, compared with thecorresponding tertiary amines, in the affinity for the substance Preceptors on human cells (IM9) without their affinity for the substanceP receptors on rat cortex being substantially reduced.

Finally, contrary to expectation, it has been found that thesequaternary salts are active in vivo and by oral administration and thatthis activity can also be exerted on the central nervous system.

Thus, according to one of its features, the present invention relates tothe quaternary ammonium salts of variously substituted aromatic aminecompounds of the formula ##STR3## in which: J is

either a group ##STR4## in which: Ar is a phenyl which is unsubstitutedor monosubstituted or polysubstituted by a substituent selected from:hydrogen, a halogen atom, a hydroxyl, a C₁ -C₃ -alkoxy, a C₁ -C₃ -alkyland a trifluoromethyl, said substituents being identical or different; aC₃ -C₇ -cycloalkyl group; a pyridyl group; or a thienyl group;

X is hydrogen;

X' is hydrogen or is combined with X" below to form a carbon--carbonbond, or else X and X' together form an oxo group; and

X" is hydrogen or forms a carbon--carbon bond with X';

or a group ##STR5## in which: Ar is as defined above;

x is zero or one; and

X₁ is hydrogen, only when x is zero; a hydroxyl; a C₁ -C₄ -alkoxy; a C₁-C₄ -acyloxy; a carboxyl; a C₁ -C₄ -carbalkoxy; a cyano; a group--NH--CO-Alk in which Alk is a C₁ -C₆ -alkyl; a mercapto group; or a C₁-C-alkylthio group; or else X₁ forms a double bond with the carbon atomto which it is bonded and with the adjacent carbon atom in thepiperidine;

Q is a C₁ -C₆ -alkyl group or a benzyl group;

A⊖ is an anion selected for example from chloride, bromide, iodide,acetate, methanesulfonate and paratoluenesulfonate anions;

m is 2 or 3;

Ar' is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from: hydrogen, a halogenatom, preferably a chlorine or fluorine atom, a trifluoromethyl, a C₁-C₄ -alkoxy and a C₁ -C₄ -alkyl, said substituents being identical ordifferent; a thienyl; a benzothienyl; a naphthyl; or an indolyloptionally N-substituted by a C₁ -C₄ -alkyl;

R is hydrogen or a C₁ -C₆ -alkyl;

T is a group selected from: ##STR6## W being an oxygen or sulfur atom;and Z is hydrogen, M or OM when T is the group ##STR7## or M when T isthe group ##STR8## M being a C₁ -C₆ alkyl; an α-hydroxybenzyl; anα-hydroxybenzylalkyl or phenylalkyl in which the alkyl is C₁ -C₃ andwhich is unsubstituted or monosubstituted or polysubstituted on thearomatic ring by a halogen, a trifluoromethyl, a C₁ -C₄ -alkyl, ahydroxyl or a C₁ -C₄ -alkoxy; a pyridylalkyl in which the alkyl is C₁-C₃ ; a naphthylalkyl in which the alkyl is C₁ -C₃ and which isunsubstituted or substituted on the naphthyl ring by a halogen, atrifluoromethyl, a C₁ -C₄ -alkyl, a hydroxyl or a C₁ -C₄ -alkoxy; apyridylthioalkyl in which the alkyl is C₁ -C₃ ; a styryl; or asubstituted or unsubstituted mono-, di- or tri-cyclic aromatic orheteroaromatic group.

In the present description, the alkyl groups or the alkoxy groups arelinear or branched. The substituents Q are either in the axial positionor in the equatorial position.

The tertiary amines which are the precursors of the quaternary amines(I) according to the invention will hereafter be called compounds offormula (Ia): ##STR9##

Among these precursors, those of formula (Ia) in which m, Ar', R, T et Zare as defined above and J is a group ##STR10## in which Ar is asdefined above, x is zero and X₁ is hydrogen, and their salts, preferablythose which are pharmaceutically acceptable, are novel and form part ofthe invention.

More particularly, the precursors of formula (Ia'): ##STR11## in whichm, Ar', R, T and Z are as defined above, and their acid addition salts,preferably those which are pharmaceutically acceptable, are preferred.

Other precursors, namely those of formula (Ia) in which m, Ar', R and Jare as defined above, T is --C(O)-- and Z is an a-hydroxybenzyl in whichthe aromatic group is unsubstituted or monosubstituted orpolysubstituted by a halogen, a trifluoromethyl, a C₁ -C₃ -alkyl, ahydroxyl or a C₁ -C₄ -alkoxy, and their salts, preferably those whichare pharmaceutically acceptable, are novel and form part of theinvention. More particularly, the compounds of formula (Ia"): ##STR12##in which J, m, Ar', R, T and Z are as defined above, and their acidaddition salts, preferably those which are pharmaceutically acceptable,are more particularly preferred.

The salts of the compounds of formulae (Ia), (Ia') and (Ia") are thoseformed with mineral or organic acids which permit a suitable separationor crystallization of the compounds of formulae (Ia), (Ia') and (Ia"),such as picric acid or oxalic acid or an optically active acid, forexample a mandelic or camphosulfonic acid, or a pharmaceuticallyacceptable salt such as the hydrochloride, hydrobromide, sulfate,hydrogensulfate, dihydrogenphosphate, methanesulfonate, methylsulfate,maleate, fumarate, naphthalene-2-sulfonate, glycolate, gluconate,citrate or isethionate.

In particular, in formula (I), Z is a mono-, di- or tri-cyclic aromaticor heteroaromatic group which can carry one or more substituents and inwhich a carbon atom of the aromatic carbocycle or aromatic heterocycleis directly bonded to the group T, or a benzyl group which isunsubstituted or substituted on the aromatic ring by the groupsmentioned above for the substituent M=phenylalkyl.

Preferably, Z is an unsubstituted, monosubstituted or polysubstitutedphenyl group; an unsubstituted or substituted naphthyl group; or abenzyl group which is unsubstituted or substituted on the aromatic ringby a halogen, a trifluoromethyl, a C₁ -C₄ -alkyl, a hydroxyl or a C₁ -C₄-alkoxy.

When Z is a phenyl group, this can preferably be monosubstituted ordisubstituted, especially in the 2,4-position but also for example inthe 2,3-, 4,5-, 3,4- or 3,5-position; it can also be trisubstituted,especially in the 2,4,6-position but also for example in the 2,3,4-,2,3,5-, 2,4,5- or 3,4,5-position, tetrasubstituted, for example in the2,3,4,5-position, or pentasubstituted. The substituents of the phenylgroup can be: F; Cl; Br; I; CN; OH; NH₂ ; NH--CONH₂ ; NO₂ ; CONH₂ ; CF₃; C₁ -C₁₀ -alkyl, preferably C₁ -C₄ -alkyl, methyl or ethyl beingpreferred, as well as, for example, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, pentyl or n-pentyl, hexyl or n-hexyl,octyl or n-octyl, nonyl or n-nonyl or decyl or n-decyl; alkenylcontaining 2 to 10 carbon atoms, preferably 2-4 carbon atoms, forexample vinyl, allyl, prop-1-enyl, isopropenyl, butenyl or but-1-en-1-,-2-, -3- or -4-yl, but-2-en-1-yl, but-2-en-2-yl, pentenyl, hexenyl ordecenyl; alkynyl containing 2 to 10 carbon atoms, preferably 2-4 carbonatoms, for example ethynyl, prop-1-yn-1-yl, propargyl, butynyl orbut-2-yn-1-yl, pentynyl or decynyl; cycloalkyl containing 3 to 8 carbonatoms, preferably 5 or 6 carbon atoms, cyclopentyl or cyclohexyl beingpreferred, as well as, for example, cyclopropyl, cyclobutyl, 1-, 2- or3-methylcyclopentyl, 1-, 2-, 3- or 4-methylcyclohexyl, cycloheptyl orcyclooctyl; bicycloalkyl containing 4 to 11 carbon atoms, preferably 7carbon atoms, exo- or endo-2-norbornyl being preferred, as well as, forexample, 2-isobornyl or 5-camphyl; hydroxyalkyl containing 1 to 5 carbonatoms, preferably 1-2 carbon atoms, hydroxymethyl and 1- or2-hydroxyethyl being preferred, as well as, for example,1-hydroxyprop-1-yl, 2-hydroxyprop-1-yl, 3-hydroxyprop-1-yl,1-hydroxyprop-2-yl, 1-hydroxybut-1-yl or 1-hydroxypent-1-yl; alkoxycontaining 1 to 10 carbon atoms, preferably 1-4 carbon atoms, methoxy orethoxy being preferred, as well as, for example, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexyloxy,heptyloxy, octyloxy, nonyloxy or decyloxy; alkoxyalkyl containing 2 to10 carbon atoms, preferably from 2 to 6 carbon atoms, for examplealkoxymethyl or alkoxyethyl, such as methoxymethyl or 1- or2-methoxyethyl, 1- or 2-n-butoxyethyl or 1- or 2-n-octyloxyethyl;alkoxyalkoxyalkyl containing from 3 to 10 carbon atoms, preferably from4 to 7 carbon atoms, for example alkoxyalkoxymethyl such as2-methoxyethoxymethyl, 2-ethoxyethoxymethyl or 2-isopropoxyethoxymethyl,or alkoxyalkoxyethyl such as 2-(2-methoxyethoxy)ethyl or2-(2-ethoxyethoxy)ethyl; alkoxyalkoxy containing from 2 to 10 carbonatoms, preferably from 3 to 6 carbon atoms, for example 2-methoxyethoxy,2-ethoxyethoxy or 2-n-butoxyethoxy; alkenyloxy containing 2 to 10 carbonatoms, preferably 2 to 4 carbon atoms, allyloxy being preferred, as wellas, for example, vinyloxy, propenyloxy, isopropenyloxy, butenyloxy suchas but-1-en-1-, -2-, -3- or -4-yloxy, but-2-en-1-yloxy orbut-2-en-2-yloxy, pentenyloxy, hexenyloxy or decenyloxy; alkenyloxyalkylhaving 2 to 10 carbon atoms, preferably 3-6 carbon atoms, for exampleallyloxymethyl; alkynyloxy containing from 2 to 10 carbon atoms,preferably 2 to 4 carbon atoms, propargyloxy being preferred, as wellas, for example, ethynyloxy, prop-1-yn-1-yloxy, butynyloxy orbut-2-yn-1-yloxy, pentynyloxy or decynyloxy; alkynyloxyalkyl containingfrom 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms, for exampleethynyloxymethyl, propargyloxymethyl or 2-(but-2-yn-1-yloxy)ethyl;cycloalkoxy containing 3 to 8 carbon atoms, preferably 5 or 6 carbonatoms, cyclopentoxy or cyclohexyloxy being preferred, as well as, forexample, cyclopropoxy, cyclobutoxy, 1-, 2- or 3-methylcyclopentoxy, 1-,2-, 3- or 4-methylcyclohexyloxy, cycloheptyloxy or cyclooctyloxy;alkylthio containing from 1 to 10 carbon atoms, preferably 1 to 4 carbonatoms, methylthio or ethylthio being preferred, as well as, for example,n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio,tert-butylthio, pentylthio, hexylthio, octylthio, nonylthio ordecylthio; alkylthioalkyl containing from 2 to 10 carbon atoms,preferably 2 to 6 carbon atoms, for example methylthiomethyl,2-methylthioethyl or 2-n-butylthioethyl; acylamino, namely alkanoylaminocontaining from 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms,formylamino and acetylamino being preferred, as well as propionylamino,butyrylamino, isobutyrylamino, valerylamino, caproylamino orheptanoylamino, or aroylamino or benzylamino; acylaminoalkyl, preferablyalkanoylaminoalkyl containing from 2 to 8 carbon atoms, preferably 3 to6 carbon atoms, such as formylaminoethyl, acetylaminoethyl,propionylaminoethyl, n-butyrylaminoethyl, formylaminopropyl,acetylaminopropyl, propionylaminopropyl, formylaminobutyl oracetylaminobutyl, as well as propionylaminobutyl or butyrylaminobutyl;acyloxy containing from 1 to 6 carbon atoms, preferably 2 to 4 carbonatoms, acetoxy, propionyloxy or butyryloxy being preferred, as well as,for example, formyloxy, valeryloxy or caproyloxy; alkoxycarbonylcontaining from 2 to 5 carbon atoms, preferably 2 or 3 carbon atoms,methoxycarbonyl and ethoxycarbonyl being preferred, as well as, forexample, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,isobutoxycarbonyl, sec-butoxycarbonyl or tert-butoxycarbonyl;cycloalkoxycarbonyl containing from 4 to 8 carbon atoms, preferably 6 or7 carbon atoms, cyclopentoxycarbonyl and cyclohexyloxycarbonyl beingpreferred, as well as cyclopropoxycarbonyl, cyclobutoxycarbonyl orcycloheptyloxycarbonyl; alkylaminocarbonylamino containing from 2 to 4carbon atoms, such as methylaminocarbonylamino, ethylaminocarbonylaminoor propylaminocarbonylamino; dialkylaminocarbonylamino containing from 3to 7 carbon atoms, preferably 3 to 5 carbon atoms,dimethylaminocarbonylamino being preferred, as well asdi-n-propylaminocarbonylamino or diisopropylaminocarbonylamino;(pyrrolidin-1-yl)carbonylamino; cycloalkylaminocarbonylamino containingfrom 4 to 8 carbon atoms, preferably 6 or 7 carbon atoms,cyclopentylaminocarbonylamino and cyclohexylaminocarbonylamino beingpreferred, as well as cyclopropylaminocarbonylamino,cyclobutylaminocarbonylamino or cycloheptylaminocarbonylamino;alkylaminocarbonylaminoalkyl containing from 3 to 9 carbon atoms,preferably 4 to 7 carbon atoms, methylaminocarbonylaminoethyl,ethylaminocarbonylaminoethyl, ethylaminocarbonylaminopropyl andethylaminocarbonylaminobutyl being preferred, as well as, for example,methylaminocarbonylaminomethyl, n-propylaminocarbonylaminobutyl andn-butylaminocarbonylaminobutyl; dialkylaminocarbonylaminoalkylcontaining from 4 to 11 carbon atoms, for exampledimethylaminocarbonylaminomethyl, diethylaminocarbonylaminoethyl,diethylaminocarbonylaminopropyl and diethylaminocarbonylaminobutyl;(pyrrolidin-1-yl)carbonylaminoethyl; (piperidin-1-yl)carbonylaminoethyl;cycloalkylaminocarbonylaminoalkyl containing from 5 to 12 carbon atoms,preferably 8 to 11 carbon atoms, cyclopentylaminocarbonylaminoethyl,cyclopentylaminocarbonylaminopropyl, cyclopentylaminocarbonylaminobutyl,cyclohexylaminocarbonylaminoethyl, cyclohexylaminocarbonylaminopropyland cyclohexylaminocarbonylaminobutyl being preferred, as well as, forexample, cyclopropylaminocarbonylaminoethyl orcycloheptylaminocarbonylaminoethyl; alkoxycarbonylaminoalkyl containingfrom 3 to 12 carbon atoms, preferably 4 to 9 carbon atoms,methoxycarbonylaminoethyl, ethoxycarbonylaminoethyl,n-propoxycarbonylaminoethyl, isopropoxycarbonylaminoethyl,n-butoxycarbonylaminoethyl, isobutoxycarbonylaminoethyl,sec-butoxycarbonylaminoethyl, tert-butoxycarbonylaminoethyl,ethoxycarbonylaminopropyl, n-butoxycarbonylaminopropyl,ethoxycarbonylaminobutyl and n-butoxycarbonylaminobutyl being preferred,as well as, for example, n-propoxycarbonylaminopropyl,n-propoxycarbonylaminobutyl or isopropoxycarbonylaminobutyl;cycloalkoxycarbonylaminoalkyl containing from 5 to 12 carbon atoms,preferably 8 to 11 carbon atoms, cyclopentoxycarbonylaminoethyl,cyclopentoxycarbonylaminopropyl, cyclopentoxycarbonylaminobutyl,cyclohexyloxycarbonylaminoethyl, cyclohexyloxycarbonylaminopropyl andcyclohexyloxycarbonylaminobutyl being preferred, as well as, forexample, cyclopropoxycarbonylaminomethyl orcycloheptyloxycarbonylaminoethyl; carbamoylalkyl containing from 2 to 5carbon atoms, preferably 2 carbon atoms, carbamoylmethyl beingpreferred, as well as carbamoylethyl, carbamoylpropyl or carbamoylbutyl;alkylaminocarbonylalkyl containing from 3 to 9 carbon atoms, preferably3 to 6 carbon atoms, methylaminocarbonylethyl, ethylaminocarbonylmethyl,n-propylaminocarbonylmethyl, isopropylaminocarbonylmethyl,n-butylaminocarbonylmethyl, isobutylaminocarbonylmethyl,sec-butylaminocarbonylmethyl and tert-butylaminocarbonylmethyl beingpreferred, as well as, for example, ethylaminocarbonylethyl,ethylaminocarbonylpropyl, ethylaminocarbonylbutyl,n-propylaminocarbonylbutyl or n-butylaminocarbonylbutyl;dialkylaminocarbonylalkyl containing from 4 to 11 carbon atoms,preferably 4 to 8 carbon atoms, dimethylaminocarbonylmethyl,diethylaminocarbonylmethyl and di-n-propylaminocarbonylmethyl beingpreferred, as well as, for example, diethylaminocarbonylethyl,diethylaminocarbonylpropyl or diethylaminocarbonylbutyl;(pyrrolidin-1-yl)carbonylmethyl; (piperidin-1-yl)carbonylmethyl;(piperidin-1-yl)carbonylethyl; cycloalkylaminocarbonylalkyl containingfrom 5 to 12 carbon atoms, preferably 7 or 8 carbon atoms,cyclopentylaminocarbonylmethyl and cyclohexylaminocarbonylmethyl beingpreferred, as well as, for example, cyclopropylaminocarbonylmethyl,cyclobutylaminocarbonylmethyl, cycloheptylaminocarbonylmethyl,cyclohexylaminocarbonylethyl, cyclohexylaminocarbonylpropyl orcyclohexylaminocarbonylbutyl; alkylaminocarbonylalkoxy containing from 3to 10 carbon atoms, preferably 3 to 5 carbon atoms,methylaminocarbonylmethoxy being preferred, as well as, for example,methylaminocarbonylethoxy or methylaminocarbonylpropoxy;dialkylaminocarbonylalkoxy containing from 4 to 10 carbon atoms,preferably 4 to 7 carbon atoms, such as dimethylaminocarbonylmethoxy ordiethylaminocarbonylethoxy; (piperidin-1-yl)carbonylmethoxy; andcycloalkylaminocarbonylalkoxy containing from 5 to 11 carbon atoms,preferably 7 or 8 carbon atoms, such as cyclopentylaminocarbonylmethoxyor cyclohexylaminocarbonylmethoxy.

The radical Z can also be a bicyclic aromatic group. When Z is a groupsuch as naphth-1- or -2-yl, said groups can be unsubstituted or canoptionally contain one or more substituents selected from: halogens andalkyl, phenyl, cyano, hydroxyalkyl, hydroxyl, oxo, alkylcarbonylamino,alkoxycarbonyl and thioalkyl groups in which the alkyls are C₁ -C₄.

The radical Z can also be a pyridyl, thiadiazolyl, indolyl, indazolyl,imidazolyl, benzimidazolyl, quinolyl, benzotriazolyl, benzofuranyl,benzothienyl, benzothiazolyl, benzisothiazolyl, isoquinolyl,benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzodioxinyl or pyridinyl,isoxazolyl, benzopyranyl, thiazolyl-, thienyl, furyl, pyranyl,chromenyl, isobenzofuranyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl,pyridazinyl, indolizinyl, phthalazinyl, quinazolinyl, acridinyl,isothiazolyl, isochromanyl, chromanyl or carbaryl group in which one ormore double bonds can be hydrogenated, it being possible for said groupsto be unsubstituted or optionally to contain one or more substituentssuch as: alkyl, phenyl, cyano, hydroxyalkyl, hydroxyl,alkylcarbonylamino, alkoxycarbonyl and thioalkyl groups in which thealkyls are C₁ -C₄.

In formula (I), T is preferably a carbonyl group.

The substituent Ar' is preferably a phenyl group which is advantageouslysubstituted by two chlorine atoms, more particularly in the 3- and4-positions.

In the same formula (I), m is preferably 2.

The substituent J of formula (I) is advantageously a group ##STR13## inwhich Ar is phenyl, x is zero and X₃ is hydrogen or an acetylaminogroup. In advantageous compounds, Z is naphthyl, benzyl or phenyl whichare unsubstituted or substituted in the aromatic ring by a substituentselected from chlorine or fluorine and C₁ -C₄ -alkyl or -alkoxy.Preferably, Z is a benzyl group substituted by an isopropoxy group,advantageously in the 3-position, or a naphth-1-yl group substituted bya halogen atom, advantageously by a fluorine in the 4-position. Moreparticularly in these advantageous compounds, the group T is a carbonyl,the group R is hydrogen or a methyl group and Ar' is 3,4-dichlorophenyl.

Particularly preferred quaternary compounds according to the presentinvention are those of formula (I) in which simultaneously:

Z is a 3-isopropoxybenzyl or 4-fluoronaphth-1-yl group;

T is a carbonyl group;

R and Q are both methyl;

Ar' is 3,4-dichlorophenyl;

m is 2; and

A⊖ is a pharmaceutically acceptable anion, chloride or methanesulfonatebeing particularly preferred.

Among these products, those of the formula ##STR14## in which iPr isisopropyl and A⊖ is as defined above, especially the methanesulfonate,iodide or chloride ion, are potent substance P antagonists, the compoundhaving the methyl group in the axial position being particularlypreferred.

Other compounds of the formula ##STR15## in which A⊖ is apharmaceutically acceptable anion, especially methanesulfonate, iodideand chloride, are extremely valuable.

The compounds of formulae (I') and (I") are extremely potent and show ahigh affinity for the neurokinin-2 and/or -1 receptors. They thereforeconstitute the preferred feature of the present invention.

N-Methyl-N-4-(4-phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl!-3-isopropoxyphenylacetamideof the formula ##STR16## is a key intermediate for the preparation ofthe compound (I') and itself possesses a very high affinity for theneurokinin receptors. This compound, its enantiomers and its acidaddition salts, of which the pharmaceutically acceptable acid additionsalts are particularly advantageous, constitute another preferredfeature of the present invention.

According to another feature, the present invention relates to a methodof preparing the compounds of formula (I), which comprises treating acompound of formula (Ia), in which the amine group which may be presenton the substituent Z is N-protected by a customary N-protecting group,in the form of its free base, with an excess of an alkylating agent ofthe formula

    A-Q

in which A is a group capable of forming an anion and is as definedabove for (I), preferably a chloride or an iodide, and Q is as definedabove for (I), and heating the reaction mixture in an organic solventselected for example from methylene chloride, chloroform, acetone oracetonitrile, at a temperature between room temperature and the refluxpoint, for one to several hours, to give, after treatment by thecustomary methods and after deprotection if appropriate, a mixture ofthe axial and equatorial conformers of the quaternary ammonium salts.

In the case where A⊖ is a pharmacologically unacceptable anion or if inany case it is desired to obtain an anion other than that obtained atthe end of the quaternization reaction, this anion can be exchanged withanother anion, for example a chloride, by reaction with the appropriateacid, optionally by elution of the compound (I) on an ion exchange resinsuch as the resin Amberlite IRA68® or Duolite A375®.

The conformers are separated by the customary methods, for example bychromatography or recrystallization.

Each of the axial or equatorial conformers of the compounds (I), in theform of racemates or in the form of optically pure R or S enantiomers,forms part of the invention.

The compounds (Ia) are prepared by a method in which:

a) a free amine of the formula ##STR17## in which m, Ar' and R are asdefined above and E is an O-protected group such as, for example,tetrahydropyran-2-yloxy, or a group ##STR18## in which J is as definedabove, it being understood that: when J is the group ##STR19## in whichX₁ is a hydroxyl, this hydroxyl is protected, is treated either with afunctional derivative of an acid of the formula

    HO--CO-Z                                                   (III)

in which Z is as defined above, it being understood that when the groupZ contains a hydroxyl, this hydroxyl is protected, when a compound offormula (Ia) in which T is --CO-- is to be prepared,

or with an iso(thio)cyanate of the formula

    W═C═N-Z                                            (III')

in which W and Z are as defined above, when a compound of formula (Ia)in which T is --C(W)--NH-- is to be prepared,

to give the compound of the formula ##STR20## b) then, when E istetrahydropyran-2-yloxy, the tetrahydropyran-2-yl group is removed byreaction with an acid;

c) the resulting N-substituted alkanolamine of the formula ##STR21## istreated with methanesulfonyl chloride; d) the resulting mesylate of theformula ##STR22## is reacted with a secondary amine of the formula##STR23## in which J is as defined above; and e) after deprotection ofthe hydroxyl represented by X₁, if appropriate, the resulting product isconverted, if desired, to one of its pharmaceutically acceptable salts.

To prepare the novel compounds of formula (Ia) in which J is a group##STR24## in which Ar is as defined above, x is zero and X₁ is hydrogen,the compound (VI) is reacted in step (d) with a 4-Ar-piperidine (Arbeing as defined above).

More particularly, to prepare the preferred compounds of formula (Ia') ,the mesylate of formula (VI) is reacted with 4-phenylpiperidine (formulaVII, J=benzylidene), which is well known in the literature.

The functional derivative of the acid (III) used is either the aciditself, suitably activated for example by cyclohexylcarbodiimide or bybenzotriazolyl-N-oxytrisdimethylaminophosphonium hexafluorophosphonate(BOP), or else one of the functional derivatives which react withamines, for example an anhydride, a mixed anhydride, the acid chlorideor an activated ester. When Z is a group OM, the acid in question iscarbonic acid and the functional derivative used is the monochloride,namely a chloroformate Cl--CO--OM.

When the starting material used is a compound of formula (II) in which Eis a group ##STR25## the method of preparing the compounds (Ia) can berepresented and illustrated in detail by scheme 1 below: ##STR26##

In formula (IIIa) above, the acid chloride is considered as a reactivefunctional derivative of the acid (III). It is possible, however, to usea different functional derivative or to start from the free acid (III),the procedure being to couple (II') with BOP and then to add the acid(III) in the presence of an organic base such as, for example,triethylamine, in a solvent such as methylene chloride ordimethylformamide, at room temperature; the compounds (I'a) obtained areisolated and purified by the customary methods such as, for example,chromatography or recrystallization.

It is also possible to react (II') with an iso(thio)cyanate W═C═N-Z(III') in an anhydrous inert solvent such as, for example, benzene,overnight at room temperature, and then to treat the reaction mixture bythe customary methods to give the compounds (Ia").

When the starting material used is a compound of formula (II) in which Eis a tetrahydropyran-2-yloxy group, the method of the present inventioncan be represented and illustrated by scheme 2.

The reactions of the compound (II") with the reactants (IIIa) and (III')take place as described above for scheme 1, it being possible for theacid chloride (IIIa) to be replaced with a different functionalderivative or with the free acid activated for example by BOP.

The intermediate (IV') obtained in this way is deprotected by mild acidhydrolysis to give the free hydroxylated compound (V), from which themesylate (VI) is prepared in order to substitute it with a secondaryamine of formula (VII), finally giving the compounds (Ia). ##STR27##

The products of formula (Ia) obtained in this way are isolated, in theform of the free base or a salt, by the conventional techniques.

When the compound of formula (Ia) is obtained in the form of the freebase, it can be purified or crystallized by salification by means oftreatment with an acid in an organic solvent. Thus treatment of the freebase, dissolved for example in an alcohol such as isopropanol, with asolution of the chosen acid in the same solvent gives the correspondingsalt, which is isolated by the conventional techniques. Thehydrochloride, hydrobromide, sulfate, hydrogensulfate,dihydrogenphosphate, methanesulfonate, methylsulfate, oxalate, maleate,fumarate and naphthalene-2-sulfonate, for example, are prepared in thisway.

When the reaction is complete, the compounds of formula (Ia) or, moreparticularly, of formula (Ia') can be isolated in the form of one oftheir salts, for example the hydrochloride or oxalate. The free base canbe prepared by neutralization of said salt with a mineral or organicbase such as sodium hydroxide or triethylamine, or with an alkali metalcarbonate or bicarbonate such as sodium or potassium carbonate orbicarbonate.

Resolution of the racemic mixtures (Ia) or, more particularly, (Ia')enables the enantiomers to be isolated.

It is also possible to resolve racemic mixtures of the products offormula (II), especially the products of formulae (II") and (II'") orprecursors thereof, in order to prepare the enantiomers of the productsof formula (Ia) or, more particularly, of formula (Ia').

The starting compounds of formula (II) are prepared from nitriles of theformula ##STR28## in which m, E and Ar' are as defined above, byreduction of the nitrile.

To prepare the compounds of formula (II) in which R is hydrogen, thestarting nitriles of formula (VIII) are hydrogenated in an alkanol suchas ethanol, in the presence of a catalyst such as Raney nickel, and thefree primary amine can be isolated by the conventional methods.

When it is desired to prepare the compounds of formula (II) in which Ris the methyl group, the free amine, obtained by hydrogenation of thenitrile (VIII) as described above, is treated with a chloroformate, forexample with the chloroformate of the formula Cl--CO--OR₁, in which R₁is a C₁ -C₆ -alkyl, to give the carbamates of the formula ##STR29##which are then reduced by known means such as reaction with a reducingagent like, for example, a metal hydride such as sodium aluminum hydrideor lithium aluminum hydride, or with a boron hydride such as boranedimethylsulfide. The reduction is carried out in a solvent such asether, toluene or tetrahydrofuran, at a temperature between roomtemperature and 60° C. The resulting amine of the formula ##STR30## isisolated by the customary methods.

It is also possible to treat the compound of the formula ##STR31## inwhich m, E, Ar', T and Z are as defined above, with an alkyl halide inthe presence of a strong base such as, for example, a metal hydridelike, for example, sodium hydride, in an inert solvent such astetrahydrofuran heated to the reflux point, in order to prepare thecompounds (IV) in which R is other than hydrogen.

The nitriles of formula (VIII) are prepared from nitriles of the formula

    Ar'--CH.sub.2 --CN                                         (XI)

which, on alkylation with a compound of the formula

    E-(CH.sub.2)-G                                             (XII)

in which m and E are as defined above and G is a halogen atom, forexample a bromine atom, or a protected hydroxyl group; give the desiredcompounds (VIII).

The nitrites of formula (VIII) in which E is a tetrahydropyran-2-yloxygroup are synthesized from a tetrahydropyran-2-yloxy (THP-O--)derivative obtained by reaction of an alkanol of the formulaBr--(CH₂)--OH, in which m is as defined above, with dihydropyran to givethe compound ##STR32## which is then added, in the presence of an alkalimetal hydride, to the acetonitrile derivative (XI) in order to preparethe intermediate of the formula ##STR33##

The nitriles of formula (VIII) in which E is a group ##STR34## in whichJ is as defined above, are synthesized by known methods wherein anitrile derivative of the formula ##STR35## is added to chlorinatedderivatives of the formula ##STR36## in the presence of sodium amide, ina solvent such as toluene, at temperatures of between 30° and 80° C.

The chlorinated derivative (XIII) is prepared by reaction of achlorinating reagent such as thionyl chloride with the hydroxylatedderivative of the formula ##STR37## which is itself prepared from theamine of the formula (VII): ##STR38## in which, if X₁ =OH, the hydroxylgroup is optionally protected by an O-protecting group by the customarymethods, with which amine ethylene oxide is reacted if m=2 and a3-halogenopropanol is reacted if m=3.

An alternative to the preparation of the compounds (I) according to theinvention consists in reacting a tertiary amine of the formula ##STR39##in which J and Q are as defined above for (I), with the methanesulfonatecompound (VI) to give directly the quaternary ammonium compound (I) inwhich A⊖ is represented by the methanesulfonate anion. This reaction iscarried out by the customary methods well known to those skilled in theart. The methanesulfonate anion obtained in this way is then optionallyexchanged with another anion selected from A⊖ as defined above, forexample the chloride anion, using an ion exchange resin as indicatedabove.

The amines of formulae (VII) and (VII') are known in the literature. Amethod of preparing them is described in the patent GB 1060160.

The compounds according to the invention were subjected to biochemicaland pharmacological tests.

Thus the compounds according to the invention antagonize the binding ofsubstance P to its receptor with a Ki of between 0.1 and 800 nM in testsperformed on rat cortex and with a Ki of between 0.01 and 30 nM in testsperformed on the lymphoblastic cell line IM9.

The compounds of the present invention have a low toxicity; inparticular, their acute toxicity is compatible with their use as drugs.For such a use, an effective amount of a compound of formula (I) isadministered to mammals.

The compounds of the present invention are generally administered indosage units. Said dosage units are preferably formulated aspharmaceutical compositions in which the active principle is mixed witha pharmaceutical excipient.

Thus, according to another feature, the present invention relates topharmaceutical compositions containing a compound of formula (I) as theactive principle.

The compounds of formula (I) above can be used in daily doses of 0.01 to100 mg per kilogram of body weight of the mammal to be treated,preferably in daily doses of 0.1 to 50 mg/kg. In humans the dose canpreferably vary from 0.5 to 4000 mg per day, more particularly from 2.5to 1000 mg, depending on the age of the subject to be treated or thetype of treatment: prophylactic or curative.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, transdermal,topical or rectal administration, the active principles can beadministered to animals and humans in unit forms of administration,mixed with conventional pharmaceutical carriers. The appropriate unitforms of administration include oral forms such as tablets, gelatincapsules, powders, granules and solutions or suspensions to be takenorally, sublingual and buccal forms of administration, subcutaneous,intramuscular, intravenous, intranasal or intraocular forms ofadministration and rectal forms of administration.

When a solid composition in the form of tablets is prepared, the activeprinciple is mixed with a pharmaceutical vehicle such as gelatin,starch, lactose, magnesium stearate, talc, gum arabic or the like. Thetablets can be coated with sucrose or other appropriate substances orthey can be treated so as to have a sustained or delayed activity and soas to release a predetermined amount of active principle continuously.

A preparation in the form of gelatin capsules is obtained by mixing theactive principle with a diluent and pouring the mixture obtained intosoft or hard gelatin capsules.

A preparation in the form of a syrup or elixir can contain the activeprinciple together with a sweetener, which is preferably calorie-free,methylparaben and propylparaben as antiseptics, a flavoring and anappropriate color.

The water-dispersible granules or powders can contain the activeprinciple mixed with dispersants or wetting agents, or suspending agentssuch as polyvinylpyrrolidone, as well as with sweeteners or tastecorrectors.

For rectal administration, suppositories are used which are preparedwith binders melting at the rectal temperature, for example cacao butteror polyethylene glycols.

For parenteral, intranasal or intraocular administration, aqueoussuspensions, isotonic saline solutions or sterile and injectablesolutions are used which contain pharmacologically compatibledispersants and/or wetting agents, for example propylene glycol.

For administration by inhalation, an aerosol is used which contains forexample sorbitan trioleate or oleic acid, as well astrichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethaneor any other biologically compatible propellant gas.

The active principle can also be formulated as microcapsules, with oneor more carriers or additives if appropriate.

The active principle can also be presented in the form of a complex witha cyclodextrin, for example α-, β- or γ-cyclodextrin,2-hydroxypropyl-β-cyclodextrin or methyl-β-cyclodextrin.

The above-mentioned compositions can also contain other active productssuch as, for example, bronchodilators, antitussives or antihistamines.

In each dosage unit, the active principle of formula (I) is present inthe amounts appropriate to the daily doses envisaged. In general, eachdosage unit is suitably adjusted according to the dosage and theintended type of administration, for example tablets, gelatin capsulesand the like, sachets, ampoules, syrups and the like, and drops, so thatsuch a dosage unit contains from 0.5 to 1000 mg of active principle,preferably from 2.5 to 250 mg, to be administered one to four times perday.

According to another feature, the present invention relates to the useof the products of formula (I) for the preparation of drugs intended forthe treatment of physiological disorders associated with an excess oftachykinins, especially substance P, examples being more particularlydisorders of the central nervous system, neurodegenerative diseases,respiratory disorders, inflammatory diseases, disorders of thegastrointestinal system, circulatory disorders, pain and migraine. Thepresent invention also includes a method of treating said complaints atthe doses indicated above.

The intermediate compounds of formula (Ia) are prepared by the methodgiven in the present description and according to the patentapplications EP-A-428434 and EP-A-0474561. Protection of the synthesisintermediates containing amine functional groups is effected by theknown methods, for example according to EP-A-512901.

The optically pure compounds (Ia) are also obtained by the methoddescribed in the patent applications EP-A-428434 and EP-A-0474561.

The compounds of formula (Ia) in which J is ##STR40## in which Ar is asdefined above, x is zero and X₁ is hydrogen, especially the compounds offormula(Ia'), are themselves also powerful substance P antagonists, moreparticularly the compound (I'b), whose Ki is between 0.3 and 0.6 nM intests performed respectively on rat cortex and on the lymphoblastic cellline IM9.

The ¹ H nuclear magnetic resonance spectra were run at 200 MHz. The ¹³ Cnuclear magnetic resonance spectra were run at 50 MHz. The chemicalshifts are expressed in ppm.

The melting points, m.p., were measured on a Koffler heating bench.

(a) or (e) denotes the axial or equatorial position of the substituentQ.

The following Examples illustrate the invention without however implyinga limitation.

PREPARATIONS A. Aminoalcohols

Preparation I

(a) α-(2-Tetrahydropyranyloxyethyl)-2-(3,4-dichloro benzene)acetonitrile

16.5 g of an 80% dispersion of sodium hydride in oil are suspended in200 ml of dry tetrahydrofuran. A solution of 100 g of3,4-dichlorophenylacetonitrile in 500 ml of tetrahydrofuran is addeddropwise at 20° C. over 30 minutes and the reaction mixture is thenstirred at room temperature for 2 hours. The mixture is cooled to -20°C., a solution of 118 g of 1-bromo-2-tetrahydropyranyloxyethane in 100ml of tetrahydrofuran is added, the mixture is left to return to roomtemperature and, after 2 hours, a solution of 50 g of ammonium chloridein 3 liters of water is added. Extraction is carried out with 1.5 litersof ether and the extract is washed with a saturated solution of NaCl,decanted, dried over MgSO₄ and concentrated under vacuum. The residue ischromatographed on silica gel using CH₂ Cl₂ and then ethyl acetate (95/5v/v) as the eluent. The pure product fractions are concentrated undervacuum to give 118 g of an oil.

(b) 2-(2-Tetrahydropyranyloxyethyl)-2-(3,4-dichloro benzene)ethanamine

118 g of the nitrile obtained above are dissolved in 700 ml of absoluteethanol. 300 ml of concentrated aqueous ammonia are added, after whichRaney nickel (10% of the amount of starting nitrile) is added whilesweeping with nitrogen. Hydrogenation is then carried out under ahydrogen atmosphere at room temperature and ordinary pressure.

16 liters are absorbed in 4 hours. The catalyst is filtered off onCelite, the filtrate is concentrated under vacuum and the residue istaken up in a saturated solution of NaCl. After extraction with etherand drying over MgSO₄, 112 g of an oil are obtained.

(c) 2-(2-Hydroxyethyl)-2-(3,4-dichlorobenzene)ethanamine

81 g of the product obtained above according to (b) are dissolved in 38ml of methanol. 80 ml of a solution of ethyl ether saturated withhydrochloric acid are added, the temperature being maintained at between20° and 25° C. The mixture is stirred for 30 minutes at room temperatureand then concentrated to dryness. The residue is dissolved in 250 ml ofwater, washed twice with ethyl ether, rendered alkaline with a solutionof NaOH and extracted with CH₂ Cl₂. After drying over MgSO₄, the extractis concentrated to dryness under vacuum, the residue is taken up in 800ml of isopropyl ether, an insoluble material is filtered off on Celite,the filtrate is concentrated under vacuum to about 300 ml and seededwith crystals of aminoalcohol and the mixture is stirred overnight. Thecrystals are filtered off and rinsed with isopropyl ether and then withn-pentane to give 30.2 g of the expected product. M.p.=90°-91° C.

(d) 2-(2-Hydroxyethyl)-2-(3,4-dichlorobenzene)ethanamine (+)

A solution of 44.7 g of the product obtained according to step (c) abovein 300 ml of methanol is added to a boiling solution of 29 g ofD(-)-tartaric acid in 800 ml of methanol. The mixture is left to returnto room temperature and stirred for 4 hours. The product is filtered offand rinsed with ethanol and then with ether to give 34.1 g of tartrate.This is recrystallized from 1.75 l of methanol to give 26.6 g oftartrate.

α!_(D) ²⁵ =-4.2° (c=1, in H₂ O)

This tartrate is taken up in 120 ml of water, rendered alkaline with asolution of NaOH and extracted twice with CH₂ Cl₂ and the extract isdried over MgSO₄ and concentrated to dryness under vacuum. The residueis taken up in a small quantity of isopropyl ether, n-pentane is addedand the mixture is filtered to give 15.4 g of the expected product.M.p.=79°-80° C.

α!_(D) ²⁵ =+9.4° (c=1, in CH₃ OH)

(e) N-Methyl-2-(2-hydroxyethyl)-2-(3,4-dichlorobenzene)ethanamine (+)Hydrochloride (e1) Ethyl N-4-hydroxy-2-(3,4-di-chlorophenyl)butyl!carbamate

15 g of the product obtained according to step (d) above are dissolvedin 200 ml of CH₂ Cl₂. 9.9 ml of triethylamine are added. The mixture iscooled to 0° C. and a solution of 6.3 ml of ethyl chloroformate in 30 mlof CH₂ Cl₂ is added dropwise at this temperature. After 15 minutes, themixture is washed with water, then with a dilute solution of HCl andthen with a saturated aqueous solution of NaHCO₃. After drying overMgSO₄, it is concentrated to dryness under vacuum to give 20 g ofproduct in the form of an oil.

(e2) Reduction of the Ethoxycarbonyl Group to a Methyl Group

A solution of 20 g of the product obtained according to step (e1) abovein 150 ml of anhydrous THF is added to 5.1 g of a suspension of lithiumaluminum hydride in 60 ml of anhydrous THF. The mixture is refluxed for1 hour. It is hydrolyzed with 20 ml of water, the inorganic material isfiltered off and the filtrate is concentrated to dryness under vacuum.The oil obtained is dissolved in 100 ml of acetone. Ethyl ethersaturated with hydrochloric acid is added to pH=1, after which ethylether is added until turbidity appears. The mixture is stirred for 1hour and the crystals are filtered off and rinsed with a small quantityof acetone and then with ethyl ether to give 11 g ofN-methyl-2-(2-hydroxyethyl)-2-(3,4-dichlorobenzene)ethanaminehydrochloride. M.p.=129° C.

α!_(D) ²⁵ =+8.4° (c=1, in CH₃ OH)

(f) N-Methyl-2-(2-hydroxyethyl)-2-(3,4-dichlorobenzene)ethanamine (-)Hydrochloride

The (-) enantiomer is obtained by following the above procedure andstarting from L(+)-tartaric acid. M.p.=129° C.

α!_(D) ²⁰ =-8.4° (c=1, in CH₃ OH)

B. Phenylacetic Acids

Preparation II.1

3-Isopropoxyphenylacetic Acid

3-Isopropoxyphenylacetic acid is not known in the literature but can beprepared by well-known methods of preparing alkoxyphenylacetic acids.

(a) Ethyl 3-hydroxyphenylacetate

A solution of 55 g of 3-hydroxyphenylacetic acid in 400 ml of 100°ethanol is refluxed overnight in the presence of a few drops ofconcentrated H₂ SO₄. It is evaporated to dryness under vacuum and theresidue is taken up in ethyl ether and washed with water and then with asaturated aqueous solution of NaHCO₃. After drying over MgSO, followedby evaporation, 58 g of an oil are obtained.

(b) Ethyl 3-Isopropoxyphenylacetate

A solution of 58 g of the product obtained above, 88 g of K₂ CO₃ and 108g of 2-iodopropane in 300 ml of DMF is heated at 80°-100° C. for 8hours. The DMF is evaporated off under vacuum and the residue is takenup in ethyl acetate and washed with a 10% aqueous solution of K₂ CO₃.After drying over MgSO₄ followed by evaporation, the residue is purifiedby chromatography on silica gel using CH₂ Cl₂ as the eluent. This gives61 g of an oil.

(c) 3-Isopropoxyphenylacetic Acid

A solution of 31 g of the product obtained above and 20 g of NaOH in 400ml of ethanol is refluxed for 2 hours. It is evaporated to dryness andthe residue is taken up in water and acidified with concentrated HCl.Extraction is carried out with ethyl ether and the extract is washedwith water, dried over MgSO₄ and concentrated to dryness under vacuum togive 27 g of the expected acid. M.p.=33°-35° C.

3-Ethoxyphenylacetic acid is prepared in the same way.

Preparation II.2

(3-Isopropoxyphenyl)hydroxyacetic Acid (a) 3-Isopropoxybenzaldehyde

50 g of 3-hydroxybenzaldehyde are dissolved, under nitrogen, in 250 mlof DMF. 60 g of K₂ CO₃ and then 60 ml of 2-iodopropane are added and thereaction mixture is heated for 18 hours at 50° C. and poured into 2.5liters of water. Extraction is carried out with ethyl ether and theether phase is washed with a dilute solution of NaOH, dried over MgSO₄and concentrated under vacuum to give 53.5 g of an oil.

(b) (3-Isopropoxyphenyl)hydroxyacetonitrile

0.72 g of sodium bisulfite is added to a suspension of 1 g of theproduct prepared above in 3 ml of water. The mixture is left for 18hours at room temperature, a solution of 0.85 g of KCN in 2 ml of wateris then added and the reaction mixture is stirred for 30 minutes.Extraction is carried out with ethyl ether and the extract is washedwith water, dried over Na₂ SO₄ and concentrated under vacuum to give 1.2g of the expected compound in the form of an oil.

(c) (3-Isopropoxyphenyl)hydroxyacetic Acid

A mixture of 1 g of the product obtained above in 1.1 ml of water and1.1 ml of concentrated HCl is refluxed for one hour. The solution isleft to cool and extracted with ethyl ether and the ether phase iswashed with water and extracted with a dilute solution of NaOH. Theaqueous phase is acidified with HCl and then extracted with ethyl etherand the extract is dried over MgSO₄ and concentrated under vacuum. Theacid is crystallized from an isopropyl ether/pentane mixture (50/50) togive 0.42 g of the expected product; m.p.=94° C.

C. Acyl Derivatives and Sulfonyloxy Derivatives

Preparation III

1. Acylation via the Acid2-(2-Hydroxyethyl)-2-(3,4-dichlorophenyl)-N-(3-isopropoxyphenyl)-N-methylacetamide

6.05 ml of triethylamine and then 5.05 g ofN-methyl-2-(2-hydroxyethyl)-2-(3,4-dichlorobenzene)ethanamine, preparedaccording to EP-A-474561, and 7.08 g of BOP are added to a solution of2.8 g of 3-isopropoxyphenylacetic acid in 50 ml of CH₂ Cl₂. Afterstirring for 4 hours at room temperature, the mixture is concentratedunder vacuum and the residue is taken up in ethyl acetate and washedsuccessively with water, with a dilute solution of NaOH and with asaturated solution of NaCl. The organic phase is dried over MgSO₄,filtered and concentrated under vacuum and the residue ischromatographed on silica gel using CH₂ Cl₂ /AcOEt (96/4 v/v) as theeluent. Concentration of the pure product fractions gives 7.0 g of theexpected acylated compound.

2. Acylation via the Acid Chloride2-(2-Hydroxyethyl)-2-(3,4-dichlorophenyl)-N-methylthiophene-2-carboxamide(-)

8.4 ml of triethylamine are added to a suspension of 8.1 g of theproduct obtained according to PREPARATION I (e) above in 120 ml ofmethylene chloride. The mixture is cooled to 0° C. and a solution of2.97 g of 2-thenoyl chloride in 35 ml of methylene chloride is addeddropwise. After 15 minutes, the mixture is washed with water, with adilute solution of HCl and then with an aqueous solution of NaHCO₃. Itis dried over MgSO filtered and concentrated to dryness under vacuum togive 9.0 g of a solid, which is taken up in ethyl ether and filteredoff. M.p.=107°-108° C.

α!_(D) ²⁰ =-47.2° (c=1, CH₃ OH)

Preparation IV

1. N-4-(2-Methanesulfonyloxy)-2-(3,4-dichlorophenyl)butyl!-N-methyl-3-isopropoxyphenylacetamide

11.7 g of the product prepared above according to PREPARATION III 1. aredissolved in 100 ml of CH₂ Cl₂ in the presence of 6.68 g oftriethylamine, and 6.94 g of methanesulfonyl chloride are then addeddropwise. The reaction mixture is left overnight at room temperature andthen concentrated under vacuum. The residue is taken up in ethyl acetateand washed successively with water and with a saturated solution of NaCland the organic phase is decanted, dried over MgSO₄, filtered andconcentrated under vacuum. The residual oil is concentrated on silicagel using CH₂ Cl₂ /CH₃ OH (99/3 v/v) as the eluent. Concentration of thepure product fractions gives 11.04 g of the expected mesylate.

2. N-Methyl-N-4-(2-methanesulfonyloxy)-2-(3,4-dichlorophenyl)butyl!thiophene-2-carboxamide(-)

4.8 ml of triethylamine are added to a solution of 10.71 g of theproduct obtained according to PREPARATION III 2. above in 120 ml ofmethylene chloride. The mixture is cooled to 0° C. and 2.7 ml ofmethanesulfonyl chloride are added dropwise. After 15 minutes, themixture is washed twice with water and then with a saturated aqueoussolution of NaCl. It is dried over MgSO₄, filtered and concentrated todryness under vacuum to give a foam.

D. Amine Derivatives

Preparation V

1. N-4-(4-Phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl!-N-methyl-3-isopropoxyphenylacetamideHydrochloride

2 g of the compound obtained according to PREPARATION IV 1. and 1.41 gof 4-phenylpiperidine are dissolved in 10 ml of DMF and the reactionmixture is heated at 70° C. for 3 hours. The solution is concentratedunder vacuum, the residue is taken up in AcOEt and washed successivelywith water and with a saturated solution of NaCl and the organic phaseis decanted, dried over MgSO₄, filtered and concentrated under vacuum.The residue is chromatographed on silica gel using CH₂ Cl₂ /CH₃ OH (97/3v/v) as the eluent. The pure product fractions are concentrated undervacuum, the base thus obtained in the form of an oil is then dissolvedin ethyl ether, and gaseous hydrochloric acid is bubbled into thesolution in order to prepare the hydrochloride of the base. 0.27 g ofthe expected product is obtained. M.p.=89°-91° C.

2. N-4-(4-Hydroxy-4-phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl!-N-methylthiophene-2-carboxamide(-)

12.12 g of the product obtained according to PREPARATION IV 2. above and11.8 g of 4-hydroxy-4-phenylpiperidine are dissolved in 30 ml of DMF andheated at 70° C. for one and a half hours. The solution is poured into30 ml of iced water and a precipitate is filtered off and dried. Theprecipitate obtained is purified by chromatography on silica gel usingCH₂ Cl₂ /CH₃ OH (90/10 v/v) as the eluent. The pure product fractionsare concentrated under vacuum and the residue is then crystallized fromether. M.p.=120°-121° C.

The hydrochloride is prepared in acetone by the addition of a solutionof ethyl ether saturated with hydrochloric acid to pH=1. The precipitateis filtered off and dried.

α!_(D) ²⁰ =-51.0° (c=1, CH₃ OH)

3. N-4-(4-Hydroxy-4-phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl!-N-methyl-4-fluoro-1-naphthylamideHydrochloride

1.5 g of N-methyl-N-4-(2-methanesulfonyloxy)-2-(3,4-dichlorophenyl)butyl!-4-fluoro-1-naphthylamideand 1.28 g of 4-hydroxy-4-phenylpiperidine are heated at 80°-90° C. in 8ml of DMF for 3 hours. The reaction mixture is left to return to roomtemperature and then poured into water, extraction is carried out withethyl acetate and the organic phase is washed successively with waterand with a saturated solution of NaCl. The organic phase is then driedover. MgSO₄, filtered and concentrated under vacuum. The residual oil ischromatographed on silica gel H using CH₂ Cl₂ /CH₃ OH (98/2 v/v) as theeluent. The hydrochloride of the pure product fractions is prepared andthen recrystallized from a mixture of acetone and ethyl acetate to give2.1 g of the expected product. M.p.=180 ° C.

4. N-4-(4-Benzylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl!-N-methyl-3-ethoxy-1-phenylacetamideHydrochloride

2 ml of triethylamine and then 2.2 g of BOP are added to a solution of 2g ofN-(4-benzylpiperidin-1-yl)-2-(3,4-dichlorophenyl)-N-methylbutylamine and0.8 g of 3-ethoxyphenylacetic acid in 40 ml of CH₂ Cl₂. The reactionmixture is left for one hour at room temperature and then concentratedunder vacuum. The residue is taken up in ethyl acetate and washedsuccessively with water, with a dilute solution of NaOH and with asaturated solution of NaCl. The organic phase is dried over MgSO₄,filtered and concentrated under vacuum. The residue is purified bychromatography on silica gel using CH₂ Cl₂ /CH₃ OH (100+1.7 v/v) as theeluent. The hydrochloride of the pure product fractions is prepared and1.65 g of the expected hydrochloride are obtained. M.p.=130° C.

5. N-4-(4-Benzylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl!-N-methyl-3,5-dimethoxyphenylacetamideHydrochloride

The expected product is obtained by following the above procedureaccording to PREPARATION V 4. and using 3,5-dimethoxyphenylacetic acid,prepared according to Tetrahedron Letters, 1991, 32, 23, 2663-2666.M.p.=150° C.

The compounds of formula (Ia) which are non-quaternary precursors of thecompounds (I) according to the invention, listed in Table A below, wereprepared using the PREPARATIONS indicated above.

                                      TABLE A                                     __________________________________________________________________________     ##STR41##                                                                     ##STR42##  m Ar.sup.1     R  Z            F.; °C.                     __________________________________________________________________________     ##STR43##  3                                                                                ##STR44##   CH.sub.3                                                                          ##STR45##   121                                 ##STR46##  2                                                                                ##STR47##   CH.sub.3                                                                          ##STR48##   123                                 ##STR49##  2                                                                                ##STR50##   CH.sub.3                                                                          ##STR51##   134                                 ##STR52##  2                                                                                ##STR53##   CH.sub.3                                                                          ##STR54##   enantiomere (-) 140                 ##STR55##  3                                                                                ##STR56##   H                                                                                 ##STR57##   121                                 ##STR58##  2                                                                                ##STR59##   H                                                                                 ##STR60##   132                                 ##STR61##  2                                                                                ##STR62##   H                                                                                 ##STR63##   124                                __________________________________________________________________________

EXAMPLE 1 (Compound 1) ##STR64##

2 g of N-4-(4-benzylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl!-4-fluoro-1-naphthylamide,prepared as indicated above according to EP-A-428434, are dissolved in20 ml of methyl iodide. The solution is stirred at room temperature for24 hours and then concentrated under vacuum. The residue ischromatographed on silica gel using CH₂ Cl₂ /CH₃ OH (97/3 v/v) and thenCH₂ Cl₂ /CH₃ OH (95/5 v/v) as the eluent. The product eluted firstcorresponds to that in which the methyl in the 1-position on thenitrogen of the piperidine is in the axial position. The correspondingfraction is concentrated under vacuum to give 1.3 g of 1-3-(3,4-dichlorophenyl)-4-(4-fluoro-1-naphthoylamino)butyl!-4-benzyl-N(a)-methyl-1-piperidiniumiodide. M.p.=120°-122° C.

¹ H NMR: 7 H between 1.3 and 2.4 (2CH₂ and CH piperidine, CH₂ β); 14 Hbetween 2.45 and 3.9 (2CH₂ N piperidine, CH₂ Ar, N⊕-CH₃, N⊕-CH₂, CH Ar',NH--CH₂); 14 H between 7 and 8.2 (all the aromatic H); 1 H at 8.5 (NH);DMSO at 2.49.

EXAMPLE 2 (Compound 2) ##STR65##

0.3 g of 1-3-(3,4-dichlorophenyl)-4-(4-fluoro-1-naphthoylamino)butyl!-4-benzyl-N(e)-methyl-1-piperidiniumiodide, in which the methyl in the 1-position on the nitrogen of thepiperidine is in the equatorial position, is obtained by following theprocedure described above in Example 1 and collecting the fractioneluted second. M.p.=120°-122° C.

¹ H NMR: 7 H between 1.3 and 2.4 (2CH₂ and CH piperidine, CH₂ β); 14 Hbetween 2.45 and 4 (2CH₂ N piperidine, CH₂ Ar, N⊕-CH₃, N⊕-CH₂, CH Ar',CH₂ --NH); 14 H between 7 and 8.3 (all the aromatic H); 1 H at 8.6 (NH);DMSO at 2.49.

EXAMPLE 3 (Compound 3) ##STR66##

1-3-(3,4-Dichlorophenyl)-4-(N-methyl-3-ethoxyphenyl-1-acetamido)butyl!-4-benzyl-N(a)-methyl-1-piperidiniumiodide is prepared by following the procedure according to Example 1 andusing N-4-(4-benzylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl!-N-methyl-3-ethoxy-1-phenylacetamideas the starting material. M.p.=90° C.

EXAMPLE 4 (Compound 4) ##STR67##

1-3-(3,4-Dichlorophenyl)-4-(N-methyl-3-ethoxyphenyl-1-acetamido)butyl!-4-benzyl-N(e)-methyl-1-piperidiniumiodide is prepared by following the procedure according to Example 2 andusing N-4-(4-benzylpiperidin-1-yl)-3-(3,4-dichlorophenyl)butyl!-N-methyl-3-ethoxy-1-phenylacetamideas the starting material. M.p.=105° C.

EXAMPLE 5 (Compound 5) ##STR68##

1 g of the iodide obtained according to Example 3 (compound 3) isdissolved in 5 ml of 95° ethanol. 40 ml of Duolite A375® resin areconditioned in the chloride form and the solution prepared above iseluted on this column, which is then rinsed with 95° ethanol. The eluateis concentrated under vacuum and the residue is taken up in ether. Themixture is filtered to give 0.69 g of 1-3-(3,4-dichlorophenyl)-4-(N-methyl-3-ethoxyphenyl-1-acetamido)butyl!-4-benzyl-N(a)-methyl-1-piperidiniumchloride. M.p.=105° C.

EXAMPLE 6 (Compound 6) ##STR69##

By following the above procedure according to Example 1, thepiperidinium iodide of N-4-(4-hydroxy-4-phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl!-N-methylthiophene-2-carboxamide(-), described above according to PREPARATION V 2., is prepared byalkylation with methyl iodide. The compound in which the methyl is inthe axial position on the nitrogen of the piperidine, namely 1-3-(3,4-dichlorophenyl)-4-(N-methyl-2-thenoylamino)butyl!-4-hydroxy-4-phenyl-N(a)-methyl-1-piperidinium(-) iodide, is eluted first. M.p.=150° C.

α!_(D) ²⁰ =-44.9° (c=1, CH₃ OH)

EXAMPLE 7 (Compound 7) ##STR70##

The quaternary salt of 1-3-(3,4-dichlorophenyl)-4-(N-methyl-2-thenoylamino)butyl!-4-hydroxy-4-phenyl-N(e)-methyl-1-piperidinium(-) iodide, in which the methyl in the 1-position on the nitrogen of thepiperidine is in the equatorial position, is obtained by following theprocedure according to Example 6 and collecting the compound elutedsecond. M.p.=130° C.

α!_(D) ²⁰ =-5.1° (c=1, CH₃ OH)

EXAMPLE 8 (Compound 8) ##STR71##

0.53 g of 1-3-(3,4-dichlorophenyl)-4-(N-methyl-3-isopropoxyphenylacetylamino)butyl!-4-phenyl-N(a)-methyl-1-piperidiniumiodide is obtained, as the first fraction eluted in chromatography, byfollowing the procedure according to EXAMPLE 1 and reacting 1.1 g of N-4-(4-phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl!-N-methyl-3-isopropoxyphenylacetamide,prepared according to PREPARATION V 1., with 10 ml of methyl iodide.M.p.=105°-107° C.

¹³ C NMR: N⊕-CH₃ : 33; N⊕-CH₂ : 56.

EXAMPLE 9 (Compound 9) ##STR72##

1-3-(3,4-Dichlorophenyl)-4-(N-methyl-3-isopropoxyphenylacetylamino)butyl!-4-phenyl-N(e)-methyl-1-piperidiniumiodide is obtained by following the procedure of EXAMPLE 8 andcollecting the second fraction eluted in chromatography. M.p.=112°-114°C.

¹³ C NMR: N⊕-CH₃ : 44; N⊕-CH₂ : 46.

EXAMPLE 10 (Compound 10) ##STR73## A) 6 g of ditert-butyl dicarbonate in25 ml of AcOEt are added to a solution of 5.85 g of2-(2-hydroxyethyl)-2(3,4-dichlorobenzene)ethanamine, obtained accordingto PREPARATION I (c), in 150 ml of AcOEt and the mixture is left at roomtemperature for 20 minutes and then refluxed for 30 minutes. It isconcentrated under vacuum to give 8.35 g of tert-butyl N-4-hydroxy-2-(3,4-dichlorophenyl)butyl!carbamate.

B) 4 ml of triethylamine and 2.14 ml of mesyl chloride are added at -20°C. to a solution of 8.35 g of the carbamate obtained above in 100 ml ofCH₂ Cl₂. The reaction mixture is stirred at 0° C. for 2 hours and thenextracted with diethyl ether. The ether phase is dried over MgSO₄,filtered and concentrated under vacuum to give 9.87 g of tert-butyl N-4-methanesulfonyloxy-2-(3,4-dichlorophenyl)butyl!carbamate.

C) 9.87 g of the mesylate prepared above and 8.05 g of4-phenylpiperidine are dissolved in 20 ml of DMF and the reactionmixture is heated at 60° C. for 2 hours. 100 ml of water are added andextraction is carried out with AcOEt. The organic phase is decanted andthen successively dried over Na₂ SO₄, filtered and concentrated undervacuum to give 11.8 g of tert-butyl N-4-(4-phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl!carbamate.

D) A solution of 11.8 g of the product prepared above in 30 ml ofanhydrous THF is added to a suspension of 2.9 g of lithium aluminumhydride in 40 ml of anhydrous THF and the reaction mixture is refluxedfor 2 hours. It is hydrolyzed by the addition of 15 ml of water, theinorganic material is filtered off and the filtrate is concentratedunder vacuum. The residue is taken up in 20 ml of CH₂ Cl₂ and 10 ml of asolution of diethyl ether saturated with HCl and the mixture is thenconcentrated under vacuum to give 6.7 g of N-4-(4-phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl!-N-methylamine,which crystallizes from acetone.

E) 3.17 ml of triethylamine, 1.40 g of (3-isopropoxyphenyl)hydroxyaceticacid, obtained according to PREPARATION II 2., and 3.14 g of BOP areadded successively to a solution of 3 g of the amine prepared above in60 ml of CH₂ Cl₂. The reaction mixture is stirred at room temperaturefor one hour and then washed successively with water and with a solutionof NaHCO₃. The organic phase is decanted, dried over Na₂ SO₄, filteredand concentrated under vacuum. The residue is chromatographed on silicagel using CH₂ Cl₂ /CH₃ OH (97/3 v/v) as the eluent. Concentration of thepure product fractions gives an oily residue, to which a solution ofdiethyl ether saturated with HCl is added to give 2 g of N-4-(4-phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl!-N-methyl-.alpha.-hydroxy-(3-isopropoxyphenyl)acetamidedihydrochloride.

F) Methyl iodide is reacted with the acetamide prepared above, under thesame conditions as for the previous Examples, to give 1-3-(3,4-dichlorophenyl)-4-(N-methyl-α-hydroxyphenylacetamido)butyl!-4-phenyl-N(a)-methyl-1-piperidiniumiodide; m.p.=130° C.

EXAMPLE 11 (Compound 11) ##STR74##

1- 4-(3,4-Dichlorophenyl)-5-(benzylN-methylcarbamate)pentyl!-4-phenyl-4-acetylamino-N(a,e)-methyl-1-piperidiniumiodide is obtained by reacting methyl iodide with benzyl N-methyl-N-5-(4-acetylamino-4-phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)pentyl!-N-carbamateunder the same conditions as for the previous EXAMPLES; m.p.=133° C.

Compounds 12 to 36 described in TABLES I and II below are prepared byfollowing the procedure of the previous PREPARATIONS and of EXAMPLES 1to 11 above.

                                      TABLE I                                     __________________________________________________________________________     ##STR75##                                                                    Exemple n.sup.o                                                                     ##STR76##  Q.sup.(1)                                                                         C.sup.(2)                                                                         R  Z            F.; °C.                       __________________________________________________________________________    12                                                                                  ##STR77##  CH.sub.3 (a)                                                                      (+, -)                                                                            CH.sub.3                                                                          ##STR78##   127                                  13                                                                                  ##STR79##  CH.sub.3 (a)                                                                      -25, 6                                                                            CH.sub.3                                                                          ##STR80##   158-160                              14                                                                                  ##STR81##  CH.sub.3 (a)                                                                      (+, -)                                                                            CH.sub.3                                                                          ##STR82##   129-145                              15                                                                                  ##STR83##  CH.sub.3 (e)                                                                      (+, -)                                                                            CH.sub.3                                                                          ##STR84##   136-155                              16                                                                                  ##STR85##  CH.sub.3 (a)                                                                      (+, -)                                                                            CH.sub.3                                                                          ##STR86##   100                                  17                                                                                  ##STR87##  CH.sub.3 (e)                                                                      (+, -)                                                                            CH.sub.3                                                                          ##STR88##   115                                  18                                                                                  ##STR89##  CH.sub.3 (a)                                                                      (+, -)                                                                            CH.sub.3                                                                          ##STR90##   125-127                              19                                                                                  ##STR91##  CH.sub.3 (e)                                                                      (+, -)                                                                            CH.sub.3                                                                          ##STR92##   162-164                              20                                                                                  ##STR93##  CH.sub.3 (a)                                                                      -35, 5                                                                            CH.sub.3                                                                          ##STR94##   101-103                              21                                                                                  ##STR95##  CH.sub.3 (e)                                                                      -7, 6                                                                             CH.sub.3                                                                          ##STR96##   105-107                              22                                                                                  ##STR97##  CH.sub.3 (a)                                                                      -31, 9                                                                            CH.sub.3                                                                          ##STR98##   162-164                              23                                                                                  ##STR99##  CH.sub.3 (e)                                                                      +1, 9                                                                             CH.sub.3                                                                          ##STR100##  154-156                              24                                                                                  ##STR101## CH.sub.3 (a)                                                                      (+, -)                                                                            CH.sub.3                                                                          ##STR102##  157                                  __________________________________________________________________________     .sup.(1) : Configuration of the substituent Q: (a) = axial, (e) =             equatorial;                                                                   .sup.(2) : Absolute configuration of the asymmetric carbon and                α.sub.D in ° at 25° C., C = 1 in CH.sub.3 OH.        

                                      TABLE II                                    __________________________________________________________________________     ##STR103##                                                                   Exemple                                                                       n.sup.o                                                                            x Q.sup.(1)                                                                         m Ar'        Z            F.; °C.                           __________________________________________________________________________    25   0 CH.sub.3 (a)                                                                      2                                                                                ##STR104##                                                                               ##STR105##  130-132                                  26   0 CH.sub.3 (e)                                                                      2                                                                                ##STR106##                                                                               ##STR107##  125-127                                  27   1 CH.sub.3 (e)                                                                      3                                                                                ##STR108##                                                                               ##STR109##  132                                      28   1 CH.sub.3 (a)                                                                      3                                                                                ##STR110##                                                                               ##STR111##  123                                      29   1 CH.sub.3 (a)                                                                      2                                                                                ##STR112##                                                                               ##STR113##  128-130                                  30   1 CH.sub.3 (e)                                                                      2                                                                                ##STR114##                                                                               ##STR115##  116-118                                  31   1 CH.sub.3 (a)                                                                      2                                                                                ##STR116##                                                                               ##STR117##  124                                      32   1 CH.sub.3 (e)                                                                      2                                                                                ##STR118##                                                                               ##STR119##  143                                      33   1 CH.sub.3 (a)                                                                      2                                                                                ##STR120##                                                                               ##STR121##  134                                      34   1 CH.sub.3 (e)                                                                      2                                                                                ##STR122##                                                                               ##STR123##  138                                      35   1 CH.sub.3 (a)                                                                      2                                                                                ##STR124##                                                                               ##STR125##  135-140                                  36   1 CH.sub.3 (e)                                                                      2                                                                                ##STR126##                                                                               ##STR127##  98                                       __________________________________________________________________________     .sup.(1) : Configuration of the substituent Q: (a) = axial, (e) =             equatorial.                                                              

What is claimed is:
 1. N-4-(4-Phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl!-N-methyl-3-isopropoxyphenyl-acetamideor a pharmaceutically acceptable salt thereof.
 2. N-4-(4-Phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl!-N-methyl-3-isopropoxyphenyl-acetamidehydrochloride.
 3. N-4-(4-phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl!-N-methyl-α-hydroxy-(3-isopropoxyphenyl)acetamideor a pharmaceutically acceptable salt thereof.